Viral hepatitis is a general term that is reserved for infections of the liver caused by one of at least five distinct hepatitis viruses--hepatitis viruses A, B, C, D and E. Regardless of etiology, the course of acute viral hepatitis is similar and can be divided into four clinical phases: (a) the incubation period, representing time between exposure and the first days of symptoms or jaundice, (b) a prodromal or preicteric stage, (c) the icteric phase, and (c) the convalescent period. The incubation period for viral hepatitis type B ("HBV") ranges from 45 to 120 days and is affected by several factors such as the size of the inoculum and virus-host interactions. Barker, L. F. and Maynard, J. E., 1972, Am. J Med. Sci. 263: 27-33.
In the United States, chronic liver disease is among the ten leading causes of death in men. Nearly 50% of these deaths are in individuals less than 60 years of age. Unfortunately, the vast majority of patients with chronic hepatitis B remain asymptomatic for many years even though there may be biochemical evidence of the disease. Viral hepatitis continues to be a major public health problem. In 1993, 43,012 cases of hepatitis were reported yielding a reported incidence of about 17 cases per 100,000 people. Centers for Disease Control and Prevention. Final 1993 Reports of Specified Notable Diseases. MMWR 1994, 43: 597-603. About one third of these cases were designated as hepatitis B.
Chronic infections with HBV affect more than 200 million persons world wide. These have a high risk of development of cirrhosis and hepatocellular carcinoma. Feitelson, M., 1992, Clin. Micro. Rev. 5: 275-301. Termination of chronic hepatitis infection may prevent the development of these sequelae. Nucleic acid based vaccines have the potential for use in mass immunizations because of the cost and ease with which they can be combined to generate multivalent immunogens. The high rate of vertical transmission of HBV in Asia and Africa poses a great problem--how to treat and terminate chronic HBV infection.
Attempts have been made to terminate chronic HBV infection with conventional HBV vaccine, with some success. In two reports of studies employing standard three dose immunization regimens, 3/14 and 11/42 patients became negative for HBV DNA. Pol, S. et al., 1993, CR. Acad. Sci. III 7: 688-691; and Pol, S. et al., 1994, Lancet 344, 342. Fazle Akbar, S. M., 1997, J. Hepatology 26: 131-137, reported that repeated monthly immunization of HBV transgenic mice with HBsAg in Freund's complete adjuvant given intraperitoneally cleared HBsAg in 25/32 mice. This strategy cannot be directly applied to man due to the toxicity of Freund's complete adjuvant.
Mancini, et al reported clearance of circulating HBsAg, and liver HBV RNA from transgenic mice encoding the HBV genome with the core gene deleted, following immunization with a single injection of a plasmid encoding S and Pre-S2 determinants of HBV. Mancini, M., 1996, Proc. Natl. Acad. Sci. USA 93: 12496-12501. Duck hepatitis B virus recombinant vaccinia virus has also been used in an attempt to terminate chronic duck hepatitis B infection. Ma, Z. M., Kong, Y. Y., Wang, Y., Wen, Y. M., 1996, Acta Virologica 40: 311-314. A temporary drop in surface antigen titer, but no permanent resolution, was observed.
Immunotherapeutic treatment of chronically infected subjects following administration of DNA-based immunization to induce termination of HBV DNA replication with HBsAg determinants have not been carried out or evaluated in chronically infected mammals heretofore.